Journal of Antimicrobial Chemotherapy (1977) 3, 435^443
Pharmacokinetics of cefazolin in patients with normal and impaired renal function
T. Bergan, £. K. Brodwall and O. 0rjavik
Intramuscular doses of 0-5 g cefazolin were given to 17 patients with varying degrees of reduced renal functions. There was no appreciable lag time before the start of absorption. In the patients with glomemlar filtration rates above 90 ml/min, the peak values ranged from 23 to 51 ug/ml which occurred 0-5 to 3-5 h after the dose. The mean peak concentration was 31 ng/ml. Absorption rate was not appreciably influenced by renal function. The elimination rate was markedly influenced by reductions in renal function. With glomerular filtration rates above 90 ml/min the serum half-life was 20±0-7 h. At 20 ml/min, the half-life was some 10 h. Below 10 ml/min the biliary route appears to assume the major responsibility for excretion. With creatinine clearance values below 5 ml/min, half-life values have varied between 15 and 45 h. The distribution volume was 12-81 ±715 1 which corresponds approximately to the extra-cellular fluid volume. Introduction Cefazolin is one of the newer cephalosporins, which in vitro has advantages over other related drugs (Eastwood, Gower & Curtis, 1975; Sabath, Wilcox, Garner & Finland, 1973; Seiga, Yamaji, Miyoshi & Minagawa, 1972). It has been used with success in a large number of cases (Brenner, Kranhold & Bush, 1975; Lode, Gebert & Hendrischk, 1975). It appears well distributed in peripheral secretions (Bergan, 1974; Bryant, 1975). Its pharmacokinetics have been compared to other cephalosporins in healthy volunteers (Bergan, 1974) and in diseased patients (Bergan & Brodwall, 1972; Bergan, 0rjavik & Brodwall, 1977; Kirby & Regamey, 1973; Rathe & Ravin, 1975; Simon, Malerczyk, Brahmstaedt & Toeller, 1973) with normal function. In this paper the uptake, distribution and elimination of cefazolin has been studied in patients with different renal functions. Materials and methods Antibiotics Cefazolin (batch no. ZH 3200) for intramuscular injection was kindly supplied by Astra Lakemedel AB, Sodertalje, Sweden. This was supplied as dried powder in vials of 500 mg to be diluted in 10 ml sterile, isotonic saline immediately prior to administration. 435
Downloaded from http://jac.oxfordjournals.org/ at UB Giessen on June 15, 2015
Department of Microbiology, Institute of Pharmacy, University of Oslo and Department B of Medicine, Rikshospitalet and University of Oslo, Oslo, Norway
37 17 27 19 22 52 19 57 25 52 20 49 53 35 43 50 55
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
117 121 116 120 ND 137 ND 36 48 38 44 9 18 11 7 15 17
147 146 134 125 92 89 53 49 48 48 43 28 25 18 17 14 10
1 2 3 2,3 4 3 3 5 3 2 4 6 3 7 3 3 8
CCR (ml/min)
c,
Diagnosis *i
0-696 2-753 0-723 0-421 0-758 0-905 2-202 1-721 0-336 1057 0-454 2-410 1-318 0-715 3-551 2-374 0-433
CPAH
741 778 374 726 317 767 247 174 296 322 336 34 93 194 34 42 35
0-247 0-282 0-723 0-421 0-299 0166 0-206 0109 0143 0-128 0189 0051 00527 00598 00483 00445 00434
k,
3-36 6-34 4-83 5-41 3-67 13-60 13-5 11-59 14-36 15-58 15-99
418
2-47 2-46 0-96 1-65 2-32
'•
0-241 0-271 0078 0-127 0126 0-381 0153 0121 0-219 0-392 0075 0189 0169 0190 0190 0134 0157
A
Ci = Inulin clearance; CCR = endogenous creatinine clearance; CPAH = p-aminohippuric acid clearance; ki — absorption constant (h"1); kt — elimination constant (h"1); '* = serum half-life (h). 1 = Benign haematuria; 2 = nephrotic syndrome; 3 = chronic glomerulonephritis; 4 = disseminated lupus erythematosus; 5 = renal artery stenosis; 6 = nephrocalcinosis; 7 = amyloid kidney; 9 = transplant with rejection.
Age
Patient N o .
Table I. Renal function and serum disposition rates of the patients studied
Downloaded from http://jac.oxfordjournals.org/ at UB Giessen on June 15, 2015
437
Pharmacokinetics of cefazolin
Subjects Seventeen patients were included in the study. All gave their informed consent to participate in the project. The patients had varying glomerular filtration rates as measured by inulin clearance (C,), endogenous creatinine clearance (CCR), and clearance of paraaminohippuric acid ( C P A H ) - The clearance values, diagnosis, and other characteristics of patients appear in Table I. Dosage Patients received 500 mg cefazolin intramuscularly and remained supine during the day of study. No other antibiotic was taken concomitantly.
Assays The cefazolin concentrations were determined by an agar well diffusion method similar to one described previously using Staphylococcus aureus ATCC 6538p as test organism (Bergan & Oydvin, 1972). The assay standard was desiccated cefazolin powder of certified potency obtained from Astra Lakemedel AB. The experimental error of the assay was 4, 7 and 9% when the concentrations of cefazolin tested were 2, 5 and 10 ug/ml. Pharmacokinetic calculations The pharmacokinetic characteristics were calculated as previously described by Bergan (1977a). Statistics Statistical estimations were calculated according to Weber (1972). 80 60 40
i
20
Pa1.l6,C| =M ml/min
f IO § 8
I
6
Pat.2,C| = 146 ml/mm i
I
2
4
I
6
i
I
8
i
I
i
10
12 14 Hours
I
i
I
i
I
16
i
18
20
22
24
Figure 1. Typical curves of serum concentrations in one patient with a normal and in one with a reduced renal function.
Downloaded from http://jac.oxfordjournals.org/ at UB Giessen on June 15, 2015
Sampling Blood was withdrawn from the antecubital vein 0, 0-5, 1, 2, 3-5, 6, 8, 12 and 24 h after drug administration and in one patient with a Ct = 10 ml/min also after 48 h. Only patients without detectable antibiotic activity in the serum sample prior to injection were accepted for the study. The serum samples were frozen at —70°C until assayed.
438
T. Bergan, E. K. Brodwall and O. 0rjavik
Results
Serum concentrations Typical curves showing serum levels attained in patients with normal or impaired renal function are shown in Figure 1. Individual peaks in 5 subjects with C\ above 90 ml/min ranged from 23 to 51 ug/ml and were found 0-5 to 3-5 h after medication. In patients with impaired renal function, the peaks tended to be higher and occurred slightly later than in normal renal function.
50
70 90 110 C\ (ml/min)
130
150
Figure 2. Relationship between elimination rate, kt, and inulin clearance, C,. Regression: 0027+0002C,; r = 0-88; i >
Pharmacokinetics of cefazolin in patients with normal and impaired renal function
T. Bergan, £. K. Brodwall and O. 0rjavik
Intramuscular doses of 0-5 g cefazolin were given to 17 patients with varying degrees of reduced renal functions. There was no appreciable lag time before the start of absorption. In the patients with glomemlar filtration rates above 90 ml/min, the peak values ranged from 23 to 51 ug/ml which occurred 0-5 to 3-5 h after the dose. The mean peak concentration was 31 ng/ml. Absorption rate was not appreciably influenced by renal function. The elimination rate was markedly influenced by reductions in renal function. With glomerular filtration rates above 90 ml/min the serum half-life was 20±0-7 h. At 20 ml/min, the half-life was some 10 h. Below 10 ml/min the biliary route appears to assume the major responsibility for excretion. With creatinine clearance values below 5 ml/min, half-life values have varied between 15 and 45 h. The distribution volume was 12-81 ±715 1 which corresponds approximately to the extra-cellular fluid volume. Introduction Cefazolin is one of the newer cephalosporins, which in vitro has advantages over other related drugs (Eastwood, Gower & Curtis, 1975; Sabath, Wilcox, Garner & Finland, 1973; Seiga, Yamaji, Miyoshi & Minagawa, 1972). It has been used with success in a large number of cases (Brenner, Kranhold & Bush, 1975; Lode, Gebert & Hendrischk, 1975). It appears well distributed in peripheral secretions (Bergan, 1974; Bryant, 1975). Its pharmacokinetics have been compared to other cephalosporins in healthy volunteers (Bergan, 1974) and in diseased patients (Bergan & Brodwall, 1972; Bergan, 0rjavik & Brodwall, 1977; Kirby & Regamey, 1973; Rathe & Ravin, 1975; Simon, Malerczyk, Brahmstaedt & Toeller, 1973) with normal function. In this paper the uptake, distribution and elimination of cefazolin has been studied in patients with different renal functions. Materials and methods Antibiotics Cefazolin (batch no. ZH 3200) for intramuscular injection was kindly supplied by Astra Lakemedel AB, Sodertalje, Sweden. This was supplied as dried powder in vials of 500 mg to be diluted in 10 ml sterile, isotonic saline immediately prior to administration. 435
Downloaded from http://jac.oxfordjournals.org/ at UB Giessen on June 15, 2015
Department of Microbiology, Institute of Pharmacy, University of Oslo and Department B of Medicine, Rikshospitalet and University of Oslo, Oslo, Norway
37 17 27 19 22 52 19 57 25 52 20 49 53 35 43 50 55
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
117 121 116 120 ND 137 ND 36 48 38 44 9 18 11 7 15 17
147 146 134 125 92 89 53 49 48 48 43 28 25 18 17 14 10
1 2 3 2,3 4 3 3 5 3 2 4 6 3 7 3 3 8
CCR (ml/min)
c,
Diagnosis *i
0-696 2-753 0-723 0-421 0-758 0-905 2-202 1-721 0-336 1057 0-454 2-410 1-318 0-715 3-551 2-374 0-433
CPAH
741 778 374 726 317 767 247 174 296 322 336 34 93 194 34 42 35
0-247 0-282 0-723 0-421 0-299 0166 0-206 0109 0143 0-128 0189 0051 00527 00598 00483 00445 00434
k,
3-36 6-34 4-83 5-41 3-67 13-60 13-5 11-59 14-36 15-58 15-99
418
2-47 2-46 0-96 1-65 2-32
'•
0-241 0-271 0078 0-127 0126 0-381 0153 0121 0-219 0-392 0075 0189 0169 0190 0190 0134 0157
A
Ci = Inulin clearance; CCR = endogenous creatinine clearance; CPAH = p-aminohippuric acid clearance; ki — absorption constant (h"1); kt — elimination constant (h"1); '* = serum half-life (h). 1 = Benign haematuria; 2 = nephrotic syndrome; 3 = chronic glomerulonephritis; 4 = disseminated lupus erythematosus; 5 = renal artery stenosis; 6 = nephrocalcinosis; 7 = amyloid kidney; 9 = transplant with rejection.
Age
Patient N o .
Table I. Renal function and serum disposition rates of the patients studied
Downloaded from http://jac.oxfordjournals.org/ at UB Giessen on June 15, 2015
437
Pharmacokinetics of cefazolin
Subjects Seventeen patients were included in the study. All gave their informed consent to participate in the project. The patients had varying glomerular filtration rates as measured by inulin clearance (C,), endogenous creatinine clearance (CCR), and clearance of paraaminohippuric acid ( C P A H ) - The clearance values, diagnosis, and other characteristics of patients appear in Table I. Dosage Patients received 500 mg cefazolin intramuscularly and remained supine during the day of study. No other antibiotic was taken concomitantly.
Assays The cefazolin concentrations were determined by an agar well diffusion method similar to one described previously using Staphylococcus aureus ATCC 6538p as test organism (Bergan & Oydvin, 1972). The assay standard was desiccated cefazolin powder of certified potency obtained from Astra Lakemedel AB. The experimental error of the assay was 4, 7 and 9% when the concentrations of cefazolin tested were 2, 5 and 10 ug/ml. Pharmacokinetic calculations The pharmacokinetic characteristics were calculated as previously described by Bergan (1977a). Statistics Statistical estimations were calculated according to Weber (1972). 80 60 40
i
20
Pa1.l6,C| =M ml/min
f IO § 8
I
6
Pat.2,C| = 146 ml/mm i
I
2
4
I
6
i
I
8
i
I
i
10
12 14 Hours
I
i
I
i
I
16
i
18
20
22
24
Figure 1. Typical curves of serum concentrations in one patient with a normal and in one with a reduced renal function.
Downloaded from http://jac.oxfordjournals.org/ at UB Giessen on June 15, 2015
Sampling Blood was withdrawn from the antecubital vein 0, 0-5, 1, 2, 3-5, 6, 8, 12 and 24 h after drug administration and in one patient with a Ct = 10 ml/min also after 48 h. Only patients without detectable antibiotic activity in the serum sample prior to injection were accepted for the study. The serum samples were frozen at —70°C until assayed.
438
T. Bergan, E. K. Brodwall and O. 0rjavik
Results
Serum concentrations Typical curves showing serum levels attained in patients with normal or impaired renal function are shown in Figure 1. Individual peaks in 5 subjects with C\ above 90 ml/min ranged from 23 to 51 ug/ml and were found 0-5 to 3-5 h after medication. In patients with impaired renal function, the peaks tended to be higher and occurred slightly later than in normal renal function.
50
70 90 110 C\ (ml/min)
130
150
Figure 2. Relationship between elimination rate, kt, and inulin clearance, C,. Regression: 0027+0002C,; r = 0-88; i >
